Recognition of the essential role of dendritic cells (DCs) as professional antigen-presenting cells has prompted investigators to search for methods to use DCs as natural adjuvants in
immunotherapy. A number of antigenic
oligopeptides, recognized by CD8(+) cytotoxic T lymphocytes (CTLs) specific for
cancer cells, have been applied in clinical trials using DCs. Such a monovalent
vaccine with a single
epitope for a particular type of HLA class 1 molecule would be effective. However, a
polyvalent vaccine might be more potent. We designed a novel
protein delivery system consisting of hydrophobized
polysaccharides complexed with target
proteins. The truncated HER2
protein encompassing 147 N-terminal
amino acids, including the 9-mer HER2p63-71
peptide (
HER2p63),
TYLPTNASL, the human homologue of an antigenic murine
tumor rejection
peptide, was prepared. We report here that HLA-A2402(+) DCs could incorporate hydrophobized
polysaccharide-truncated HER2
protein complexes and process the
protein to present major histocompatibility complex class 1-binding
HER2p63 peptide. The complexes enter DCs by phagocytosis, and then the truncated
protein is processed through a pathway similar to that for endogenous
proteins. DCs sensitized by these complexes primed and boosted HER2p63-specific CD8(+) T cells in the context of HLA-A2402. Vaccination with DCs incorporating these complexes completely suppressed lung
metastases in a HER2-expressing murine
tumor model. We also generated 3 CD4(+) clones reactive with different HER2- derived 25-mer
peptides from lymph node cells in mice treated with CHP/HER2-147. Thus, hydrophobized
polysaccharide-
protein complexes are promising candidates for the construction of
polyvalent vaccines.